The Acute Toxicity of Inhaled Beryllium Metal in Rats

The Acute Toxicity of Inhaled Beryllium Metal in Rats. HALEY,P. J., FINCH, G. L., HOOVER, M. D., AND CUDDIHY, R. G. (1990).Fundam. Appl. Toxicol. 15, 767–778. We exposed rats onceby nose only for 50 min to a mean concentration of 800 µg/m³of beryllium metal (initial lung burden, 625 µg) to characterizethe acute toxic effects within the lung. Histological changeswithin the lung and enzyme changes within bronchoalveolar lavage(BAL) fluid were evaluated at 3, 7, 10, 14, 31, 59, 115, and171 days postexposure (dpe). Beryllium metal-exposed rats developedacute, necrotizing, hemorrhagic, exudative pneumonitis and intraalveolarfibrosis that peaked at 14 dpe. By 31 dpe, inflammatory lesionswere replaced by minimal interstitial and intraalveolar fibrosis.Necrotizing inflammation was observed again at 59 dpe whichprogressed to chronic-active inflammation by 115 dpe. This inflammationworsened progressively, as did alveolar macrophage and epithelialhyperplasia, becoming severe at 171 dpe. Low numbers of diffuselydistributed lymphocytes were also present but they were notassociated with granulomas as is observed in beryllium-induceddisease in man. Throughout the experiment, total numbers ofcells were elevated within the BAL samples due primarily toincreased numbers of neutrophils. Lymphocytes were not elevatedin BAL samples collected from beryllium-exposed rats at anytime after exposure. Lactate dehydrogenase (LDH), ß-glucuronidase,and protein levels were elevated in BAL fluid from 3 through14 dpe but returned to near normal levels by 31 dpe. LDH increasedonce again at 59 dpe and remained elevated at 171 dpe. ß-Glucuronidaseand protein levels were slightly, but not significantly, elevatedfrom 31 through 171 dpe. Results indicate that inhalation ofberyllium metal by rats results in severe, acute chemical pneumonitisthat is followed by a quiescent period of minimal inflammationand mild fibrosis. Progressive, chronic-active, fibrosing pneumonitisis observed later. Chronic beryllium lung disease of man isan immunologically mediated granulomatous lung disease, whereasberyllium-induced lung lesions in rats appear to be due to directchemical toxicity and foreign-body-type reactions.     

Detection of a Retention Wire Fracture in An Asymptomatic Patient 18 Years after Implantation

An asymptomatic patient with a Teletronics Accufix atrial lead (Teletronics, Englewood, CO, USA) presented for an annual fluoroscopic examination. The examination revealed a retention wire fracture, which occurred 18 years after the initial implantation. Annual fluoroscopic examination of these leads should still be performed. (PACE 2010; 33:246–247)     

Sleep disorders and their clinical significance in children with Down syndrome

Aim Our aim was to review basic aspects of sleep disorders in children with Down syndrome in the light of present‐day findings of such disorders in children in general, including other groups of children with developmental disabilities. Methods A literature search of adverse developmental effects of sleep disturbance, types of sleep disturbance in children with Down syndrome, their aetiology, including possible contributions of physical and psychiatric comorbidities and medication effects, principles of assessment and diagnosis, and treatment issues, was carried out. Results Sleep disturbance is particularly common in children with developmental disorders including Down syndrome. Although there are just three basic sleep problems (sleeplessness or insomnia, excessive daytime sleepiness, and parasomnias) there are many possible underlying causes (sleep disorders), the nature of which dictates the particular treatment required. In children with Down syndrome, in addition to the same influences in other children, various comorbid physical and psychiatric conditions are capable of disturbing sleep. Possible adverse medication effects also need to be considered. Interpretation Screening for sleep disorders and their causes should be routine; positive findings call for detailed diagnosis. Management should acknowledge the likely multifactorial aetiology of the sleep disorders in Down syndrome. Successful treatment can be expected to alleviate significantly the difficulties of both child and family.     

Detection of Atrial Fibrillation During Sinus Tachycardia Induced by Exercise in Patients with Implantable Atrial Defibrillators

Accurate detection of atrial fibrillation (AF) is essential for appropriate operation of an implantable atrial defibrillator (IAD). However, during episodes of sinus tachycardia, distinction between AF and sinus rhythm (SR) using the quiet interval and baseline crossing analysis in the detection algorithm of the IAD may be difficult. The efficacy of this AF detection algorithm was tested in five patients implanted with an IAD (MFTRIX, Model 3000 or 3020, InControl Inc.) during treadmill exercise testing. The IADs were programmed to Monitor Mode with a wake up cycle of 1 minute for AF detection using the device nominal parameters or modified parameters, and to mark rhythms appropriate for shock delivery. A mean peak heart rate of 137 ± 26 beats/min was reached during maximum exercise, and one patient developed transient AF. Seventy-eight (75 in SR, 3 in AF) and 91 (89 in SR, 2 in AF) runs of AF detection were performed using the nominal and modified parameters, respectively. The IAD detected AF and SR accurately, except for one episode of false-positive AF detection during sinus tachycardia at the nominal settings, but inappropriate shocks were prevented by minimum RR interval criteria that limited discharge at high heart rate. These results indicate that the AF detection algorithm in the IAD may become more vulnerable to false-positive AF detection during sinus tachycardia, which were avoided by reprogramming the Quiet Interval and minimum RR interval criteria for AF detection. Exercise testing appeared useful to program optimal settings of the IAD in preparation for daily activities.     

Atrial Fibrillation Induction and Determination of Atrial Vulnerable Period Using Very Low Energy Synchronized Biatrial Shock in Normal Subjects and in Patients with Atrial Fibrillation

The atrial vulnerable periods (A VP)for shock induction of atrial fibrillation (AF) in humans have not been clearly defined. Furthermore, the safety and efficacy of using low energy biatrial shock delivered transvenously for AF induction are unknown. We tested the safety and efficacy of using very low energy biatrial shocks, delivered between the right atrium and the coronary sinus for AF induction and used this technique to characterize the A VP in nine controls and nine patients with AF. Thirty-volt and 60-V 3/3-ms biphasic shocks were delivered, starting from 50 ms before the atrial effective refractory period with 20-ms increments until the end of the QRS interval to determine the AVP front, AVP end, and the AVP duration. Successful AF induction could be achieved in eight (89%) of the nine controls and in nine (100%) of the nine patients with AF without any complication. In patients with AF, the AVP front started significantly earlier within the QRS complex, and the AVP duration and the AVP duration/QRS percent ratios were also significantly greater as compared to controls. Furthermore, a higher induction shock energy in patients with AF was associated with an increase in AF inducibility and significantly increased the AVP duration and A VP duration/QRS percent ratio as compared to the controls. This study demonstrated the safe and efficacy of delivering a very low energy biatrial shock during the AVP within the R wave for AF induction. The characteristics of A VP in patients with AF were significantly different from normal subjects.     

Stroke Risk Stratification in a “Real‐World” Elderly Anticoagulated Atrial Fibrillation Population

Stroke Risk Stratification . Introduction: Appropriate stroke risk stratification is essential to ensure suitable tailoring of antithrombotic therapy. The objective of this study was to assess the predictive value of stroke risk classification schemes and to identify patients with atrial fibrillation (AF) who are at substantial risk of stroke despite optimal anticoagulant therapy, in a “real world” consecutive elderly AF cohort. Methods: Six hundred and sixty‐two consecutive AF patients (mean [SD] age 74 [7.7] years; 36.1% female) referred to the Anticoagulation Clinic of the Azienda Ospedaliera Careggi of Florence, Italy, were included and followed‐up for a mean 3.6 ± 2.7 years for the incidence of thromboembolic (TE) events. The ability of the new CHA₂DS₂‐VASc schema to predict TE was compared with other contemporary stroke risk schema (including CHADS₂, NICE 2006, ACC/AHA/ESC 2006, and ACCP 2008), by determining the c‐statistic. Results: Univariate predictors of TE events were female gender (odds ratio 1.9; 95%CI [confidence intervals] 1.01–3.70) and previous stroke/transient ischemic attack (TIA)/TE (OR 5.6; 95%CI 2.70–11.45), although after adjustment only previous stroke/TIA/TE was an independent predictor of TE (OR 5.5; 95%CI 2.68–11.31; P = 0.0001). All stroke risk schema had modest discriminating ability, with c‐statistics ranging from 0.54 (atrial fibrillation investigators [AFI]) to 0.72 (CHA₂DS₂‐VASc). The CHADS₂ and CHA₂DS₂‐VASc schemes having the best c‐statistics (0.717 and 0.724, respectively) with significant discriminating value between risk strata (both P < 0.001). The proportion of patients assigned to individual risk categories varied widely across the schema, with those categorized as “moderate‐risk” ranging from 5.3% (CHA₂DS₂‐VASc) to 49.2% (CHADS₂‐classical). Conclusion: In this “real world” cohort, current published risk schemas have modest predictive ability, with the CHADS₂ and CHA₂DS₂‐VASc schemes having the best predictive value for thromboembolism. Future trials could assess the value of alternative strategies for thromboprophylaxis in high‐risk anticoagulated patients identified by these schemes. (J Cardiovasc Electrophysiol, Vol. 22, pp. 25‐30, January 2011)     

Pharmacokinetic–pharmacodynamic modeling of the hypotensive effect of remifentanil in infants undergoing cranioplasty

Objectives:  Although remifentanil has been used to induce hypotension during surgery in infants, no pharmacokinetic–pharmacodynamic (PKPD) model exists for its quantitative analysis. Our aim was to determine the quantitative relationship between whole blood remifentanil concentration and its hypotensive effect during surgery in infants.
Methods/materials:  We studied seven infants (age 0.3–1 year) who underwent cranioplasty surgery and received remifentanil delivered by a computer-controlled infusion pump during the maintenance of anesthesia. Arterial blood samples to determine remifentanil concentration and mean arterial blood pressure (MAP) measurements were collected. A simultaneous PKPD mixed-effects model was built in NONMEM.
Results:  A total of 77 remifentanil concentrations and 185 MAP measurements were collected. Remifentanil pharmacokinetics was described with a two-compartment model, parameter estimates were 2.99 l·min⁻¹·70 kg⁻¹ for clearance and 16.23 l·70 kg⁻¹ for steady state volume of distribution. Mean baseline MAP was 69.7 mmHg and was decreased as per clinical requirements. A sigmoidal E _max model driven by an effect compartment described the decrease in MAP, with an estimated concentration to decrease MAP by half (EC₅₀) being 17.1 ng·ml⁻¹.
Conclusions:  Remifentanil is effective in causing hypotension. The final model predicts that a steady state remifentanil concentration of 14 ng·ml⁻¹ would typically achieve a 30% decrease in MAP.     

Determinants of Lesion Dimensions during Transcatheter Microwave Ablation

Background: Transcatheter microwave ablation is a novel technique for treating cardiac arrhythmias. Methods: We investigated the effects of catheter temperature, application duration, and antenna length on lesion dimensions during catheter‐based microwave ablation. In a swine thigh muscle preparation, microwave was delivered at targeted temperatures of 60°C (n = 18), 70°C (n = 27), 80°C (n = 43), or 90°C (n = 18) for 120 seconds with 10‐mm antenna; and at targeted temperatures of 80°C for 120 seconds (n = 22), 150 seconds (n = 18), 180 seconds (n = 18), 210 seconds (n = 18), and 240 seconds (n = 17) with 20‐mm antenna using 10 F catheter (MedWaves, San Diego, CA, USA) during parallel orientation. Conventional radiofrequency ablation (RF) using a 4‐mm tip electrode was performed as control. Results: With 120‐second energy applications, lesion length and depth were significantly larger with targeted temperatures of 80°C and 90°C than 60°C (P< 0.05). Furthermore, lesion depth and width, but not length, were significantly increased by prolonging energy application duration from 120 to 240 seconds at targeted temperature of 80°C (P< 0.05). Compared to RF, microwave lesions were significantly longer but had comparable depth and width. A 20‐mm microwave antenna produced longer lesions than either a 10‐mm antenna or RF ablation catheter. Multivariate analysis demonstrated that targeted temperature ≥80°C, application duration ≥150 seconds, and use of 20‐mm antenna were independent predictors for lesion depth and width (P< 0.05). Surface dessication was observed in 4/18 (22%) lesions at 90°C, as compared with 1/136 (0.7%) at 80°C targeted tip temperature (P < 0.05). Conclusions: This study demonstrated that lesions size with transcatheter microwave ablation can be controlled by adjusting targeted temperature, energy application duration, and antenna length. A targeted temperature of 80°C for more than 150 seconds should provide optimal lesion dimensions and lower risk of surface dessication or charring.     

ACCURACY OF PREDICTING LONG-TERM PROSTATE SPECIFIC ANTIGEN OUTCOME BASED ON EARLY PROSTATE SPECIFIC ANTIGEN RECURRENCE RESULTS AFTER RADICAL PROSTATECTOMY

PURPOSE: We determined how prostate specific antigen (PSA) doubling time changed with time and whether an early measure of doubling time would accurately predict long-term PSA values and clinical outcome in a cohort of patients followed expectantly after radical prostatectomy. MATERIALS AND METHODS: We analyzed data on 121 patients with PSA recurrence after radical retropubic prostatectomy. Group and individual analyses were performed on 60 patients who met study inclusion criteria. PSA doubling time was calculated and a curve was plotted using logarithmic transformation with linear regression and least squares analysis. In analysis 1 patients were placed into 3 subgroups according to doubling time. Doubling time was calculated per subgroup and the slopes of the aggregate curves were compared to determine how doubling time changed with time. In analysis 2 we calculated early doubling time per patient using only the initial 2 detectable PSA values and compared it with eventual doubling time in each using all PSA values. In addition, we analyzed how doubling time correlated with the clinical course. RESULTS: Using the group methodology there was no statistically significant acceleration or deceleration with time in doubling time slope in any of the 3 subgroups. On individual analysis we noted a weak correlation of early with eventual doubling time (correlation coefficient 0.69, p = 0.01). In 88% of patients eventual doubling time was not within 10% of early doubling time. Metastasis developed in 60% of patients with an eventual DT of 0 to 6 months, while 80% with an eventual doubling time of 6 to 12 months had no evidence of local or metastatic disease. No patients with an eventual doubling time of greater than 12 months have had metastatic disease and only 4 (16%) had local recurrence, which was treated with radiation therapy. In 8 of the 14 patients (23%) with local recurrence or metastatic disease early doubling time predicted eventual doubling time. Early doubling time was more rapid and slower than eventual doubling time in 5 and 1, respectively, of the remaining cases, which would have placed them in a different subgroup. CONCLUSIONS: On group analysis PSA doubling time appeared to be constant with time and there was no evidence that it accelerated with time in our dataset of PSA recurrence after radical prostatectomy. On individual analysis early doubling time showed a weak but statistically significant correlation with eventual doubling time. However, there was significant inaccuracy when predicting PSA doubling time based on early PSA values in individuals. Generally early projections of doubling time tend to over predict tumor biological aggressiveness, that is local recurrence or metastasis. A need remains for more accurate predictors of the rate of disease progression at initial PSA recurrence to determine accurately early in the clinical course the patients who may benefit from additional therapy. Currently no patient in our study has died of prostate cancer.